The aim of this proposal is to investigate the functional neuroanatomy of depression. A promising strategy for parsing the heterogeneity of Major Depressive Disorder (MDD) is to identify phenotypes characterized by reliable functional brain abnormalities. Anhedonia, the lack of reactivity to pleasurable stimuli, is considered a trait marker for depression. Preclinical work suggests links among phenomena associated with depression - decreased hedonic responsiveness, exaggerated stress responsiveness, and dysfunction in the dopaminergic mesolimbic system - but in humans the neural underpinnings are largely unknown. Using behavioral, event-related potential (ERP), and functional magnetic resonance imaging (fMRI) techniques, this proposal aims to investigate these processes. A monetarily reinforced button-press task will be used to dissociate the neural circuitry involved in anticipation of and reactivity to reward or punishment. Experiment 1 addresses the spatio-temporal dynamics of brain mechanisms underlying anticipation of and reactivity to reward and punishment in subjects differing on objective measures of anhedonia, operationalized as decreased responsiveness to reward-related cues in a separate signal-detection task. Compared to controls, subjects with impaired reward responsiveness (n=20) are predicted to show lower activation in regions subserving reward processing (e.g., nucleus accumbens, medial prefrontal cortex) to reward-related, but not to punishment-related, cues. In the ERP data, decreased late frontal negativity wave to reward cues, and decreased medial-frontal negativity and P3 to reward feedbacks, are hypothesized. Experiment 2 extends this paradigm to subjects with a DSM-IV diagnosis of MDD. These subjects (n=23) are expected to show lower activation in regions subserving reward processing than controls (n=23) in response to reward-related cues, and higher activation in regions subserving processing of withdrawal-related cues. In the ERP data, medial-frontal negativity and P3 are predicted to differentiate the subject groups. Experiment 3 addresses the effects of mental stress on reward processing in MDD. Compared to controls (n=21), depressed subjects (n=21) are expected to show a larger stress-induced reduction of activation in regions subserving reward processing, and a larger activation in regions subserving punishment processing. Decreased gray matter density in medial and subgenual prefrontal regions, as assessed by voxel-based MRI morphometrical analyses, is expected to be associated with the detrimental effect of stress on reward responsiveness. Overall, the integration of techniques with high temporal (ERP) and spatial (fMRI) resolution will enhance understanding of the functional neuroanatomy of depression. [unreadable] [unreadable]